In DIC, microthrombi are formed in microvasculature, in the presence of a severe underlying disease. The microthrombi damage the microcirculation and cause an organ dysfunction or a bleeding tendency. The symptoms of DIC are associated with SIRS. The following three failures or reactions are observed in DIC:    (1) The microthrombus formation causes a microcirculatory failure, and a variety of organs fall into dysfunction due to ischemia.    (2) The microthrombus formation promotes a consumption coagulopathy, that is, increasing of tissue factor production on the surface of endothelial cells leads to activation of extrinsic coagulation pathway. Further, coagulation factors and platelets are consumed, and a bleeding tendency occurs.    (3) Hyperfibrinolysis, that is, the fibrinolytic system activated according to the activation of coagulation, generates plasmin, which degrades fibrin. When the α2-plasmin inhibitor (α2PI), which inhibits plasmin, is consumed and decreased to less than 60% of the normal level, fibrin is degraded by the plasmin and a bleeding tendency occurs.
In sepsis-induced DIC, cytokines generated from monocytes (macrophage), such as tumor necrosis factors (TNF-α) or interleukins (IL-1β), activate neutrophils. Active oxygen and neutrophil elastase produced from neutrophils damage vascular endothelial cells, which leads to hyperpermeability of the vascular endothelium and vasospasm. As a result, the microcirculation is damaged. Further, it is considered that monocytes per se and vascular endothelial cells are activated, and tissue factors are produced on the endothelial cell surfaces to form microthrombi. This microthrombus formation aggravates microcirculatory failure and causes multiple organ failure (MOF). According to a recent popular SIRS concept, this MOF is considered to be caused by a systemic inflammatory reaction. In adult respiratory distress syndrome (ARDS), platelets concentrate in the pulmonary circulation, and an occlusion of the pulmonary artery occurs. In SIRS, neither a reaction to a specific antigen nor an increased cytokine causes the inflammatory reaction. SIRS is a syndrome in which the inflammatory reaction is activated, without such a specific target, by nonspecifically reacting with an invasion to a living body and an uncontrollable cytokine production causes severe MOF (non-patent references 1 and 2).
SIRS is classified into noninfectious SIRS and sepsis. Noninfectious SIRS is caused by shock, injury, burn, or acute pancreatitis, and sepsis is caused by bacteremia by various pathogenic bacteria, or other severe infectious diseases. Sepsis is a biological immune response per se against an invasion of a pathogen, an injury of a tissue, or anoxia, and a nonspecific and systemic acute inflammatory reaction caused by various endogenous mediators, independently of the type of invasion. Organ failure accompanied by SIRS is sometimes caused by an inflammation or ischemia of a tissue, at the early stage. However, in the multiple organ dysfunction syndrome (MODS) caused by prolonged SIRS, biological overreactions via various mediators are involved in an aggravation of the conditions, and thus it is difficult to predict the prognosis of SIRS.
In SIRS, inflammatory cytokines such as TNF-α, IL-1 (interleukin-1), or IL-6 (interleukin-6) are increased in blood. In particular, TNF-α is considered to be a cytokine which activates neutrophils and promotes a coagulation reaction in SIRS. When the activation of neutrophils exceeds the cytoprotective functions of vascular endothelial cells, vascular endothelial cells are damaged by proteases such as neutrophil elastase or cathepsin G, and thus, the microcirculation is damaged and microthrombi are formed. The activated neutrophils accumulate not only at the irritated area, but also at distant organs such as the lungs or the liver (leukocytes easily adhere thereto due to a low perfusion pressure). It is considered that microthrombi formation causes a stasis and ischemia of tissues and, as a result, MOF is caused. Further, neutrophils infiltrate into extravasculature to damage organs. When the microthrombus formation continues, coagulation factors and platelets are consumed. When the state of SIRS continues for 3 days or more, the patient is associated strongly with DIC. As described above, DIC is closely related to SIRS.
Neutrophil elastase is a neutral protease having a molecular weight of approximately 30,000 and located in azurophile granules. Under physiological conditions, neutrophil elastase digests and degrades phagocytosed bacteria or foreign bodies on the inside of neutrophils, and digests elastin, collagen (type III, type IV), fibronectin, immunoglobulin, or coagulation factor XIII on the outside of neutrophils, to regulate the biosynthesis of tissues. Under disease conditions, neutrophil elastase inactivates biological components, such as elastic fibers, proteoglycans, collagen fibers, antithrombin III, or α2-plasmin inhibitor. When neutrophil elastase acts on a heparin binding site of antithrombin III to inactivate antithrombin III, DIC is caused. Neutrophil elastase is inactivated by α1-antitrypsin (α1-AT) which is an inhibitor of elastase for 3 msec. in blood. However, in an inflammatory tissue, it is considered that α1-AT is oxidized by active oxygen, myeloperoxidase, and/or lactoferrin released from neutrophils, and thus, neutrophil elastase is not inactivated and damage is caused to the tissue. Since neutrophil elastase shows a low substrate specificity, when neutrophil elastase is overreleased or an inhibitor such as α1-AT is decreased, there is a possibility that neutrophil elastase degrades the biological components and damages its own tissues. Severely damaged vascular endothelial cells are injured, and platelets adhere and aggregate to the injured area to form thrombi.
This adhesion of platelets requires human VWF in plasma, and triggers a series of platelet activation including a platelet aggregation and a release of intracellular granules, and then formed thrombi lead to hemostasis. In general, the VWF is secreted from vascular endothelium to blood as a macromolecule having a molecular weight of more than 20,000 kDa, and is cleaved by a metalloprotease, VWF-cleaving protease, into multimers of 500 to 20,000 kDa, which circulate through the blood. In some disease states (i.e., when a high shear stress is caused by occlusion or the like), the protein structures of the VWF change to an extended structure. The extended VWF is resistant to the VWF-cleaving protease. It is considered that when “unusually large” VWF molecules are overproduced in the blood and bind to platelets then, as a result, the platelet aggregation in blood vessels is promoted to form thrombi in microcirculation. Such thrombus formation involved in platelets is essential for physiological hemostatic mechanisms. However, activation of coagulation factors (such as factor VII or factor II) leads to the thrombus formation by fibrin formation and platelet fusion.